renu lal fda cder sbir'17 · clinical studies phase i ‐first human subject studies...

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Center for Drug Evaluation and ResearchSmall Business and Industry Assistance

(CDER SBIA) and

New Drug Review

LT Renu Lal, Pharm.D.CDER Small Business and Industry AssistanceDivision of Drug InformationCenter for Drug Evaluation and Research Food and Drug AdministrationNovember 2017

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Session Overview

CDER SBIA Program

Organizational Framework and Regulatory Authority

New Drug Development Process

Financial Incentives

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FDA Mission: Promote and protect public health

CDER Mission: Promote and protect the health of Americans by assuring that prescription and over‐the‐counter drugs are safe and effective.

CDER SBIA Mission: Engage with small pharmaceutical business and industry by providing timely and accurate information on human drug development and regulation

Mission

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CDER SBIA

FDA recognizes that regulated small business and industry may encounter some difficulties in working through the complex regulatory process

Each regulatory Center has established a small business assistance office

SBIA provides technical assistance and an efficient channel through which small business and industry can acquire information from the FDA.

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CDER SBIA ‐What We DoCDER SBIA provides the global pharmaceutical industry with information relating to the development and regulation of human drug products. Services include:

Conferences

Direct Communication

Services

CDER SBIA Chronicles & Podcasts

Webinars

Presentations & Exhibits Webpage CDERLearn

Publications ListservInteractions with Foreign Regulators

LinkedIn

www.fda.gov

6www.fda.gov

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7www.fda.gov

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SBIA Outreach Collaborative effort

[email protected]

[email protected]

[email protected]

9379 Total SBIA Inquiries 3351 emails

6028 phone calls

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FDA Organizational Framework

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FDA Organizational Framework

US Food and Drug Administration (FDA)

Office of Regulatory Affairs (ORA)

Center for Biologics Evaluation and Research (CBER)

Center for Drug Evaluation and Research (CDER)

Center for Tobacco Products (CTP)

Center for Devices and Radiological Health (CDRH)

National Center for Toxicological Research (NCTR)

Center for Veterinary Medicine (CVM)

Center for Food Safety and Applied Nutrition (CFSAN)

US Food and Drug Administration (FDA)


Center for Biologics Evaluation and Research (CBER)

Center for Drug Evaluation and Research (CDER)

Center for Tobacco Products (CTP)

Center for Devices and Radiological Health (CDRH)

National Center for Toxicological Research (NCTR)

Center for Veterinary Medicine (CVM)

Center for Food Safety and Applied Nutrition (CFSAN)

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• Lead Office for all FDA field activities

• 227 offices and 13 laboratories throughout the U.S.

– Inspections of firms and plants producing FDA‐regulated products

– Investigations of consumer complaints, emergencies and criminal activity

– Enforcement of FDA regulations

– Sample collection and analysis

– Review of imported products

CDER OND Organizational Structure

Office ofNew Drugs

Hematology & Oncology

Oncology I

Oncology II

Hematology

Hematology Oncology

Toxicology

ODE I

Cardiovascular &

Renal

Neurology

Psychiatry

ODE II

Pulmonary, Allergy

& Rheumatology

Metabolic &Endocrine

Anesthesia,Analgesia,

& Addiction

ODE III

Bone, Reproductive &

Urologic

Gastroenterology & Inborn Errors

Dermatology &Dental

Antimicrobial

Anti-Infective

Transplant &Ophthalmology

Anti-viral

ODE IV

NonprescriptionDrug Products

Medical Imaging Products

Pediatrics and Maternal Health

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Scientific Review Staff

Reviewers specialize in

Clinical (M.D.)

Pharmacology/Toxicology (Ph.D.)

Regulatory Project Management (R.N., Pharm.D.,)

Chemistry (Ph.D.)

Clinical Pharmacology/Biopharmaceutics (Ph.D., Pharm.D.)

Statistics (Ph.D.)

Microbiology (Ph.D.)

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The Role of the Review Division

Provide advice and guidance to regulated industry during drug development

Signatory authority for regulatory decisions related to new (i.e., not generic) drugs

Work in conjunction with the other offices within CDER

Establish policy and procedures governing the above

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Where Does our Regulatory

Authority Come From?

Code of Federal Regulations

Written in response to laws passed by CongressRepresents how FDA interprets the

Acts or laws which Congress passes

Several VolumesGeneral and specific sections devoted to different FDA

product

areas (e.g., drugs, devices, and

biologics)

What are Guidance Documents?

Distinctly separate from the CFR

Represent the Agency’s current thinking on a particular subject

Provide flexibility as technology and drug development processes evolve

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Regulatory Authority

CDER regulates

Based on therapeutic health claim in the

‐ application

‐ label and packaging

‐ advertising (for prescription drugs)

CDER does not regulate

the practice of medicine

compounds that do not make a health claim

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Is Your Product a Drug?

DRUG:

Is your product or product idea intended to cure, treat, mitigate, diagnose, or prevent disease in humans, or is your product (other than food) intended to affect the structure or function of the human body? Yes

Does your product achieve its primary intended purposes through chemical action and is your product metabolized by the human body? Yes

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New Drug Development Process

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Pre‐Clinical R&D

Phase 1 Phase 2 Phase 3 Phase 4FDA Review

Pre‐IND Meeting

Submit IND

SAFETYSubmit NDA/BLA Application

EFFICACY

EOP2 Meeting

Pre‐NDA/BLA Meeting

AC MeetingPost‐marketing Commitments

Labeling & Risk Evaluation Meetings

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Preclinical Research

Discovery/Screening

Synthesis and Purification

Animal Testing

Evaluate drug’s toxic

and pharmacologic effects

Determine whether the compound is safe

for use in humans

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Pre‐Clinical R&D


Pre‐IND Meeting

Submit IND


EFFICACY

EOP2 Meeting




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Investigational New Drug Application (IND)

Needed generally whenever studies in humans are conducted in the U.S. except:– Drug is lawfully marketed in the U.S. and investigation is not intended

to support change in labeling or advertising and does not change the known risk/benefit profile (Exemptions 21 CFR 312.2(b))

– Some bioavailability/bioequivalence studies (21 CFR 320.31(d))– Radioactive drugs for certain research purposes (21 CFR 361.1)

Studies not conducted under an IND still require IRB approval and informed consent

Regulations: 21 CFR 312

Guidance: INDs – Determining Whether Human Research Studies Can Be Conducted Without an IND

2017 SBIA REdI Fall Conference

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Pre‐IND Meeting

Discussion with FDA staff prior to filing IND Opportunity to discuss:

‐ Chemistry, Manufacturing, Controls (CMC) issues

‐ Preclinical studies

‐ Initial clinical protocol design

Should have data and a development strategy

Pre‐set, well defined questions FDA offers suggestions, clarifies data requirements and study design

Pre‐Clinical R&D


Pre‐IND Meeting

Submit IND


EFFICACY

EOP2 Meeting




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Clinical Studies

Phase I ‐ First human subject studies‐ Determine pharmacologic and metabolic activity, safety and maximum tolerated dosage in humans, side effects with increasing dose

Phase II‐ Determine effectiveness for a particular indication, short‐term side effects and risks, characterization of dose identification and dose response

Phase III – Large, controlled multicenter studies‐ Gathers additional safety and efficacy information, addresses special issues/populations, provides basis for physician labeling

Pre‐Clinical R&D


Pre‐IND Meeting

Submit IND

SAFETY

Submit NDA/BLA Application

EFFICACY

EOP2 Meeting




Accelerated ApprovalFast TrackPriority ReviewBreakthrough Therapies

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Accelerating Availability of New Drugs for Patients with Serious Diseases

Accelerated Approval– allows earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint

Fast Track– facilitates the development and expedites the review of drugs to treat serious diseases and fill an unmet medical need

Priority Review– reduces the time it takes FDA to review a new drug application

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Breakthrough Therapies

Expedited development and review of drugs that –- Treat serious/life-threatening disease; and

- Preliminary clinical evidence indicates that drug may

demonstrate substantial improvement over existing therapies

Features of breakthrough therapy designation include: - Frequent FDA/sponsor communications & meetings

- Cross-disciplinary project lead assigned to FDA review team

- Organizational commitment in a proactive, collaborative, cross-disciplinary review

Guidance – Expedited Programs for Serious Conditions – Drugs and Biologics

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Pre‐Clinical R&D


Pre‐IND Meeting

Submit IND


EFFICACY

EOP2 Meeting




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New Drug Application (NDA) or Biologic License Application (BLA)

contains the following:

Pre‐clinical studies

Human clinical studies

Manufacturing details

Labeling

Additional information

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Prescription DrugUser Fee Act (PDUFA)

http://www.fda.gov/oc/pdufa/

Permits CDER/CBER to charge pharmaceutical manufacturers a fee to review drug applications

Imposes deadlines (Standard: 10 months; Priority: 6 months)

These fees provide appropriate resources to accelerate the review of applications

Not the only source of funds for CDER/CBER

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PDUFA VI Enhancements

Promoting Innovation Through Enhanced Communication Between FDA and Sponsors During Drug Development

Ensuring Sustained Success of Breakthrough Therapy Program

Early Consultation on the Use of New Surrogate Endpoints

Advancing Development of Drugs for Rare Diseases

Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision‐Making

Enhancing Benefit‐Risk Assessment in Regulatory Decision‐Making

Advancing Model‐Informed Drug Development

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21st Century Cures

• Bill signed into law by President on 12/13/2016

• Impact:

– Patient experience data

– Real world evidence

– Informed consent waiver

– Limited population data

– Funding for additional FDA infrastructure

– Adaptive designs and novel statistical methods

– Surveillance edits

– Indirect: Expanded Access

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Panel of OUTSIDE experts

Provide advice and opinions to the FDA drug review team

FDA advisory committee Information:

http://www.fda.gov/AdvisoryCommittees/

Advisory Committees

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PDUFA Fees (FY 2018)

Application FeeRequiring clinical data: $2,421,495

Not requiring clinical data: $1,210,748

Program Fee (formerly Product Fee): $304,162

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NDA / BLA Review in CDER:The Final Action(s)

Complete Response (CR)

Approval (AP)

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FDAEvaluates benefits/risks for the population

Providerevaluates benefits/riskfor a patient

Patientevaluates benefits/risks in terms of personal values

B B B BB B BB

RRR

Benefits

Benefits

Risks

Risks

Pre‐Clinical R&D


Pre‐IND Meeting

Submit IND


EFFICACY

EOP2 Meeting




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Safety/adverse reaction surveillance

Product defect reporting

Marketing and advertising

Compliance

Post‐approval inspections

Post‐marketing Activities

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Financial Incentives

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Grants

Solicited grant applications Solicited through RFAs posted at http://grants.gov

https://www.fda.gov/aboutfda/business/ucm119348.htm

Unsolicited grant applicationsApplications not submitted in response to an RFA; submitted to NIH (Center for Scientific Review)

SBIR/STTR

NIH grants and funding opportunitieshttp://grants.nih.gov/grants/guide

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Orphan Drugs

For Rare Diseases and Conditions

Less than 200,000 persons

No expectation of development cost recovery

Incentives

Waiver of PDUFA application and supplement fees

Tax credit for clinical research

7 years market exclusivity (vs. 5 years)

Designation

Administered by Office of Orphan Products Development

Does not alter the standard review requirements

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Orphan Grants Programs

Orphan Products Grants ProgramGoal: to encourage clinical development of products for use in rare diseases or conditions‾ FDA provides grants for clinical studies on safety and/or effectiveness that will either result in, or substantially contribute to, market approval of these products

For information and application process/RFA postings: https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/WhomtoContactaboutOrphanProductDevelopment

NIH Office of Rare Disease Research also provides funding‐ https://rarediseases.info.nih.gov/guides/pages/124/finding‐funding‐opportunities

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PDUFA Waivers

A waiver may be granted for one or more fees where:

a waiver or reduction is necessary to protect the public health;

assessment of the user fees would present a significant barrier to innovation due to limited resources or other circumstances;

the fees will exceed the anticipated present and future costs incurred by FDA for conducting the process for the review of the new drug applications for the person;

The applicant is a small business submitting its first human drug application to the Secretary for review.

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PDUFA Waiver for Small Business

To qualify for a small business waiver, an applicant must meet all of these criteria:‐ Employs fewer than 500 employees, including affiliates;‐ Does not have a drug product that has been approved under a human

drug application and introduced or delivered for introduction into interstate commerce; and

‐ The applicant, including its affiliates, is submitting its first human drug application.

Guidance for Industry User Fee Waivers, Reductions, and Refunds for Drug and Biological products (03/11/11)

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079298.pdf

FAQs: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm069943.htm

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• Incentive to spur the development of new treatments for rare or neglected diseases

• Rare Pediatric Disease PRV & Tropical Disease PRV

– High development costs and small market

– PRV voucher allows sponsor to have any one of their drugs reviewed under FDA's priority review system

– Can be redeemed or transferred to another sponsor, to obtain priority review of another application that would otherwise be ineligible for priority review

• Application sponsor must pay a priority review user fee in addition to any other required user fee.

Priority Review Voucher

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GAIN and QIDP

• GAIN Act: Generating Antibiotics Incentives Now Act (GAIN Act)– Helps stimulate the development of new antibiotics– Certain antibacterial or antifungal drugs intended to treat serious or life‐threatening infections can be designated “Qualified Infectious Disease Products” (QIDPs)• Priority review• Can receive fast track designation• May be eligible for an additional five years of marketing exclusivity and exclusive marketing rights

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CDER SBIA Contact Information:

Phone: 866‐405‐5367 or 301‐796‐6707

Email: [email protected]

www.fda.gov/cdersbia and www.fda.gov/cdersbialearn

SBIA Email Updates: Sign up on our website

SBIA LinkedIn: https://www.linkedin.com/company/cder‐small‐business‐and‐industry‐assistance

www.fda.gov

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Biosimilars

Biological products:

Therapies used to treat diseases and health conditions

Include a variety of products including vaccines, blood and blood components, gene therapies, tissues, and proteins

Generally are made from human and/or animal materials

FDA issued guidance documents on biosimilars development to assist industry in developing biosimilar versions of approved biological products

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Biosimilar User Fee Act (BsUFA)

Authorizes FDA to assess and collect fees for biosimilar biological products

FDA dedicates these fees to expediting the review process for biosimilar biological products

http://www.fda.gov/forindustry/userfees/biosimilaruserfeeactbsufa